Conventionally, many compounds are known as medicines which act on the circulatory system, including a variety of compounds developed as vasodilators.
Among such vasodilators, .alpha..sub.1 -blockers represented by prazosin are the subject of a great deal of active development work for their merits in that (1) their antihypertensive action is strong and positive, (2) they give no adverse effect to the metabolism of lipids and carbohydrates and (3) they can be easily used even for hypertensives suffering from complication. Examples of .alpha..sub.1 -blockers which are clinically used these days can include, in addition to prazosin, bunazosin, tetrazosin, urapidil and doxazosin. Further, medicines equipped with .alpha..sub.1 -blocking action and anti-serotonin action in combination have possibility to reduce side effects induced by hypotensive action based on the .alpha..sub.1 -blocking action, such as orthostatic hypotension and reflex tachycardia, and are hence expected to become superior hypertension therapeutics.
Further, hypertensives generally have potentiated platelet-aggregating ability and tend to form thrombi, so that they are considered to develop ischemic heart diseases or peripheral circulatory disturbances. As one of factors which take part in the formation of thrombi, serotonin is known. Serotonin is a compound contained abundantly in platelets, which are a blood component, and in a central nervous system, it acts as a neurotransmitter. In platelets, it is released upon stimulation by thromboxane A.sub.2, ADP, collagen or the like, and synergistically acts on release of various platelet aggregation factors through activation of serotonin-2 receptors in the platelets and vascular smooth muscle cells and also on vasoconstriction by norepinephrine through .alpha..sub.1 receptors, thereby inducing strong platelet aggregation and vasoconstriction [P. M. Vanhoutte, "Journal of Cardiovascular Pharmacology", Vol. 17 (Supple. 5), S6-S12 (1991)].
Serotonin is also known to potentiate proliferation of vascular smooth muscle cells [S. Araki et al., "Atherosclerosis", Vol. 83, pp.29-34(1990)]. It has been considered that, particularly when endothelial cells are injured as in arteriosclerosis or myocardial infarction, the vasoconstricting action and thrombus forming action of serotonin are exasperated, thereby reducing or even stopping blood supply to myocardial, cerebral and peripheral organs [P. Golino et al., "The New England Journal of Medicine", Vol. 324, No. 10, pp.641-648(1991), Y. Takiguchi et al., "Thrombosis and Haemostasis", Vol. 68(4), pp.460-463(1992), A. S. Weyrich et al., "American Journal of Physiology", Vol. 263, H349-H358(1992)]. Being attracted by such actions of serotonin or serotonin-2 receptors, various attempts are now under way to use a serotonin-2 receptor antagonist as a pharmaceutical for ischemic diseases of the heart, the brain and peripheral tissues.
With the foregoing in view, medicines which have .alpha..sub.1 -blocking action and serotonin-2 receptor antagonistic action in combination are expected to have vasodilating action, anti-platelet action and vascular smooth muscle cell proliferation inhibitory action and are considered to become extremely effective medicines for the prevention and treatment of not only hypertension but also all circulator diseases, for example, heart failure, ischemic heart diseases such as angina pectoris, myocardial infarction and post-PTCA restenosis, cerebrovascular disturbances such as cerebral infarction and cerebral sequelae after subarachnoid hemorrhage, peripheral circulatory disturbances such as arteriosclerosis obliterans, thromboangiitis obliterans and Raynaud disease.
To date, several medicines have been reported to have .alpha..sub.1 -blocking action and serotonin-2 receptor antagonistic action in combination. They are however still accompanied with many problems to be improved in potency, selectivity to other receptors, toxicity, side effects and/or the like. There is accordingly an outstanding demand for the provision of still better compounds.